Low temperature resistant aerosol anesthetic preparation containing benzocaine



3,322,624 ILQW TEMPERATURE RESISTANT AEROSOL ANESTHETHC KREPARATJIUNCONTAINING BENZOQAHNE Raymond A. Stone, Chicago, ill, assignor toArnar-Stone Laboratories, Inc, Mount Prospect, 1111., a corporation oflliinois No Drawing. Filed Oct. l, 1964, Ser. No. 400,949

11 Claims. (Cl. 167-52) This application is a continuationin-part of mycopending application Serial No. 380,945, filed July 7, 1964, nowabandoned, entitled Aerosol Anesthetic Preparation.

This invention relates to an aerosol anesthetic preparation. Moreparticularly, this invention is concerned with a liquid anestheticpreparation in an aerosol container for topical application which ischaracterized by resistance to low temperatures. The prepartion isdesigned for relief of surface pain and itching, and provides soothingtemporary relief of minor burns, sunburn, cuts, scratches, nonpoisonousinsect bites, poison ivy, and minor skin irritations. It may also beused for post-partum care. The preparation is nonstinging andnonchilling even when applied to open cuts and wounds.

In my prior application Serial No. 380,945 there is described animproved aerosol anesthetic preparation which is characterized by beingnonstinging and nonchilling even when applied to open cuts and wounds.This prepa ration contains a high concentration of benzocaine dissolvedin a polyethylene glycol ester, and contains a liquifiedch-lorofiuoroalkane propellant which consists essentially of 70 to 100%by weight of dichlorodifluoromethane and from to 30% oftrichlorofluoromethane. In the preferred embodiment, the propellantconsists of 80 to 100% by weight of dichlorodifluoromethane and from 0to of trichlorofluoromethane. From 1.5 to- 2.5 parts of the propellantare employed per part by weight of the polyethylene glycol ester. Thesolution of the benzocaine in the polyethylene glycol ester contains atleast 10% by weight of benzocaine. The liquified propellant is misciblewith the polyethylene glycol solvent solution, and the preparationpreferably consists of a substantially single phase system, although thebenzocaine is not appreciably soluble in the propellant. A highproportion of the propellant, particularly the high proportion of thedichlorodifluoromethane, makes it difficult to maintain the desiredconcentration of benzocaine in solution, especially at temperaturesbelow ordinary room temperature, as may be encountered in the storage,shipping, or use of such preparations.

One of the solvents which has been in commercial use for some years insuch preparations is a polyethylene glycol diester formed from mixedcoconut oil fatty acids. When this solvent was tried 'in preparationsformulated as described in pending application Serial No. 380,945, itwas found that a single phase system could not be achieved at normal usetemperatures while employing the desired high ratio of the aerosolpropellant to the benzocaine solvent. When the propellant is present asa separate phase and is only partial-1y dissolved in the solvent-benzocaine phase, the preparation is rendered less stable, and benzocainecrystals tend to form and collect at the interface. Since the spraynozzles of aerosol containers have small orifices, even a small amountof benzocaine crystals can cause clogging of the nozzle. Under moreextreme conditions, as when the temperature is lowered, a substantialportion of the benzocaine can crystallize and settle out in thecontainer. With a system containing two liquid phases or where solidparticles of benzocaine are present, it is difiicult to avoid settlingof the contents of the aerosol container, and at the very least it isnecesshanghai Patented May 30, 1196? sary to shake the containervigorously before applying the preparation. Otherwise, the preparationwill be applied in a nonhomogeneous form.

A different but somewhat related problem arises when it is desired tostore or use such preparations at temperatures below ordinary roomtemperature. If the temperature is reduced to a point where a multiplephase system results or where the preparation becomes partiallysolidified or frozen, the benzocaine is thrown out of solution, and itis dilficult or impossible to get all of the benzocaine back in solutionmerely by such expedients as warming the aerosol container to roomtemperature, shaking the container, etc. Such preparations cannot beused at temperatures during winter weather conditions in most of theUnited States.

It is therefore a principal object of the present invention to providean improved formulation for an aerosol anesthetic preparation whichsubstantially overcomes the problems and difficulties described above.More specifically, it is an object to provide a nonstinging andnonchilling liquid anesthetic preparation suitable for packaging in anaerosol container which can be formulated as a single phase system, andwhich is characterized by ease of reconstitution to its single phasestate if the preparation is stored at low temperatures and even if thepreparation becomes solidified or frozen. In certain embodiments thepreparations of this invention are particularly adaptable for use at lowtemperatures, since the preparations remain as single phase liquidsystems down to temperatures as low as 0 F. Further objects andadvantages are indicated in the following detailed specification.

This invention is based on the discovery that nonstinging, nonchillingaerosol anesthetic preparations can be prepared While at the same timeproviding preparations which are single phase systems and which aretemperature resistant, being easily reconstitutatable and/or adapted foruse at low temperatures. Specifically, it was discovered that the alkylchain length in the ester groups is critical for achieving theseobjectives, when the preparation utilizes the propellant mixturedescribed in Serial No. 380,945 and a high concentration of benzocaine.Fatty acids derived from coconut oil are normally regarded as havingrelatively short alkyl groups, as compared with the fatty acids derivedfrom other naturally occurring fats and oils. For example, a typicalanalysis of coconut oil shows that it contains from 60 to 65% of fattyacids (principally lauric acid) having chain lengths of C to C and from35 to 40% of fatty acids (principally myristic acid) having chainlengths of from C to C Nevertheless, during the experimental Workleading to the present invention, it was found that polyethylene glycoldiesters formed from mixed coconut oil fatty acids, such as the diesterof nonaethylene glycol, failed to produce preparations which could bepacked and distributed as essentially single phase systems.

The foregoing problem was not solved until it was discovered that thesolvent should be formed of diesters wherein the alkyl groups arecomposed substantially entirely of C to C chain lengths. Morespecifically, the polyethylene glycol ester solvent for the benzocaineshould contain at least by weight of compounds represented by theformula 0 0 II I! R '(J O(CHZCH20)D C RI wherein n is an integer from 7to 15 and R and R are alkyls containing from 7 to 11 carbons.Preferably, the solvent is composed substantially entirely to ofcompounds falling within the above formula.

The polyethylene glycol portion of the solvent molecule can beconveniently provided by starting with compounds such as PolyethyleneGlycol 400 (or Carbowax 400) which are composed predominantly ofnonaethylene glycol. As indicated, the number of ethylene glycol groupsin the compound may vary from 7 to 15. Optimally from 8 to 10 ethyleneglycol groups are present. A mixed polyethylene glycol can be used wherethe predominate or average chain lengths correspond with the ranges setout. Such polyethylene glycol compounds can be esterified with C to Cfatty acids or with mixtures thereof including specifically caprylic,pelargonic, capric, undecanoic, and lauric acids. Specific preferredcompounds are polyethylene glycol dicaprylate, dipelargonate, dicaprate,and dilaurate. Other suitable compounds include the caprate caprylate,the laurate caprylate, the caprylate pelargonate, the lauratepelargonate, the laurate caprate, and the caprate pelargonate.

In practicing the present invention, it is desirable that the propellantconsist of at least 70% (viz. from 70 to 100%) by weight ofdichlorodifluoromethane. From to 30% of trichlorofluoromethane based onthe total weight of the propellant can also be included. The utilizationof a propellant containing at least 80% (viz. from 80 to 100%) by weightof dichlorodifluoromethane and from 0 to 20% of trichlorofluoromethaneis preferred. For example, an optimum formulation comprises 80 to 95%dichlorodifiuoromethane in admixture with to 20% trichlorofluoromethane.

In practicing the present invention, it is desirable to employ at leastone part by weight of the propellant (total) per part of the solvent.Preferably, at least 1.5 parts of the propellant are employed per partof solvent. For example, for each part of solvent, from 1.5 to 2.5 partsof propellant can be used.

The solvent solution (excluding the propellant) should contain at leastby weight of benzocaine. It will be understood that this is based on thecombined weight of the benzocaine and solvent. In certain preferredembodiments, at least by weight of benzocaine is present in the solventsolution. The benzocaine concentration can range up to about 22%. Itwill be understood of course that the benzocaine can only be employed upto its saturation solubility in the solvent solution, or in the mixtureof the solvent solution with the propellant.

This invention is further illustrated by the following specificexamples.

Example 1 A single phase, temperature resistant aerosol topicalanesthetic is prepared according to the following formulation:

Formulation A: Wt. percent Nonaethylene glycol (Polyethylene Glycol Inpreparing the formulation, the benzocaine is dissoived in thenonaethylene glycol .dilaurate at room temperature (e.g. 70 F.). Thesolvent solution is then introduced into the aerosol containers in amanner well known in the art. After the spray nozzle components havebeen applied and the container closed, the propellant is introduced as apremixed liquid. The containers are then shaken to form a single liquidphase. The preparation is easily reconstitutable if a multiple phasesystem results from temperature reduction or after the preparation issolidified by freezing.

If desired, small quantities of auxiliary agents may be incorporated inthe formula, such as oil-soluble antiseptics like benzethonium chloride,oxyquinoline, oxyquinolinebenzoate, hexachlorophene, etc.

4 Example 2 Another aerosol preparation is produced as described inExample 1, except that the following formulation is used:

Formulation B: Wt. percent Nonaethylene glycol (Polyethylene Glycol 400)caprate caprylate 28.9 Benzocaine 5.8 Dichlorodifiuoromethane 55.4Trichlorofiuoromethane 9.9

The preparation of Formulation B is particularly useful under relativelycold conditions. The product remains as a single liquid phase in thecontainer down to temperatures as low as 0 F.

Example 3 Additional preparations can be prepared by procedures similarto that used for the preparation of Examples 1 and 2, but utilizing oneof the following formulations:

Formulation C: Wt. percent Nonaethylene glycol (Polyethylene GlycolWhile in the foregoing specification this invention has been describedin relation to certain preferred embodiments thereof, and many detailshave been set forth for purposes of illustration, it will be apparent tothose skilled in the art that the invention is susceptible to otherembodiments and that many of the details described herein can be variedconsiderably without departing from the basic principles of theinvention.

I claim:

1. A liquid anesthetic preparation in an aerosol container, saidreparation consisting essentially of a single phase mixture of aliquefied chlorofiuoroalkane propellant and a solution of benzocaine ina polyethylene glycol diester solvent, said propellant being selectedfrom the group consisting of dichlorodifiuoromethane, and mixtures ofdichlorodifluoromethane with trichlorofiuoromethane, at least 1.5 partsby weight of said propellant being employed per part of said solvent,said propellant containing at least 70% by weight ofdichlorodilluoromethane, said solution of said benzocaine in saidsolvent containing at least 10% benzocaine by Weight, said solventconsisting essentially of polyethylene glycol diesters at least byweight of which diesters are represented by the formula wherein n is aninteger from 7 to 15 and R and R are alkyls containing from 7 to 11carbons.

2. The anesthetic preparation of claim 1 in which the diestersrepresented by said formula are nonaethylene glycol diesters havingester groups selected from the group consisting of dilaurate, capratecaprylate, dicaprate, dipelargonate, and mixtures of said diesters.

3. The anesthetic preparation of claim 1 in which the diestersrepresented by said formula comprise from to 100% by weight of the totalpolyethylene glycol diesters of said solvent.

4. The anesthetic preparation of claim 3 in which the diestersrepresented by said formula are nonaethylene glycol diesters havingester groups selected from the group consisting of dilaurate, capratecaprylate, dicaprate, dipelargonate, and mixtures of said diesters.

5. The anesthetic preparation of claim 2 in which said ester groups aredilaurate.

6. The anesthetic preparation of claim 2 in which said ester groups arecaprate caprylate.

7. A liquid anesthetic preparation in an aerosol container, saidpreparation consisting essentially of a single phase mixture of aliquefied chlorofluoroalkane propellant and a solution of benzocaine ina polyethylene glycol diester solvent, said propellant being a mixtureof dichlorodifluoromethane with trichlorofluoromethane and containing atleast 70% by weight of said dichlorodifluoromethane, from 1.5 to 2.5parts by weight of said propellant being employed per part of saidsolvent, said solution of said benzocaine in said solvent containing atleast by weight of benzocaine, said solvent consisting essentially ofpolyethylene glycol diesters at least 90% by Weight of which diestersare represented by the formula:

0 R-i Jo(oHzoHz0).. :-R1 wherein n is an integer from 7 to and R and Rare alkyls containing from 7 to 11 carbons.

References Cited UNITED STATES PATENTS 2,457,188 12/1948 Stone 167-522,713,019 7/1955 Jefiries 16763 2,801,201 7/1957 Kipnis 167-82 OTHERREFERENCES Carbowax Polyethylene Glycols for Pharmaceuticals andCosmetics Booklet, Union Carbide Chemicals Company, New York, N.Y., 1962page 5.

ALBERT T. MEYERS, Primary Examiner. JULIAN S. LEVITT, Examiner. JEROMED. GOLDBERG, Assistant Examiner.

1. A LIQUID ANESTHETIC PREPARATION IN AN AEROSOL CONTAINTER, SAIDPREPARATION CONSISTING ESSENTIALLY OF A SINGLE PHASE MIXTURE OF ALIQUEFIED CHLOROFLUOROALKANE PROPELLANT AND A SOLUTION OF BENZOCAINE INA POLYETHLENE GLYCOL DIESTER SOLVENT, SAID PROPELLANT BENG SELECTED FROMTHE GROUP CONSISTING OF DICHLORODIFLUOROMETHANE, AND MIXTURES OFDICHLORODIFLUOROMETHANE, WITH TRICHLOROFLUOROMETHANE, AT LEAST 1.5 PARTSBY WEIGHT OF SAID PROPELLANT BEING EMPLOYED PER PART OS SAID SOLVENT,SAID PROPELLANT CONTAINING AT LEAST 70% BY WEIGHT OFDICHLORODIFLUOROMETHANE, SAID SOLUTION OF SAID BENZOCAINE IN SAIDSOLVENT CONTANING AT LEAST 10% BENZOCAINE BY WEIGHT, SAID SOLVENTCONSISTING ESSENTIALLY OF POLYETHYLENE GLYCOL DIESTERS AT LEAST 90% BYWEIGHT OF WHICH DIESTERS ARE REPRESENTED BY THE FORMULAR-COO-(CH2-CH2)N-CO-R1 WHEREIN N IS AN INTEGER FROM 7 TO 15 AND R AND R1ARE ALKYLS CONTAINING FROM 7 TO 11 CARBONS.